experiences with non-0157 stec and implications on public
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Experiences with non-O157 Experiences with non-O157 STEC and implications on STEC and implications on Public Health ProgramsPublic Health Programs
FLEMMING SCHEUTZFLEMMING SCHEUTZ
STATENS SERUM INSTITUTSTATENS SERUM INSTITUT
The International The International EscherichiaEscherichia and and KlebsiellaKlebsiella Centre (WHO) Centre (WHO)
CopenhagenCopenhagen
Publications “O157”, “non-O157”, Publications “O157”, “non-O157”,
VTEC, STEC & Shiga-Like Toxin in VTEC, STEC & Shiga-Like Toxin in
Title/Abstract in PubMed (1982 - Title/Abstract in PubMed (1982 -
2007)2007)
0
50
100
150
200
250
300
350
400
450
500
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
O157 referencesNon-O157 references
VTECSTEC
Shiga-Like Toxin
Non-O157 STEC studiesNon-O157 STEC studiesK. E. Johnson et al. CID 2006;43K. E. Johnson et al. CID 2006;43
16 countries, 1988-2006 (1,402/2,892)16 countries, 1988-2006 (1,402/2,892)48%48%
Range 19%-100%Range 19%-100%USA, Canada, UK, Germany, Spain, Italy, Czech Republic, Belgium, USA, Canada, UK, Germany, Spain, Italy, Czech Republic, Belgium, France, Denmark, Finland, Sweden, Australia, Chile, Argentina & Japan France, Denmark, Finland, Sweden, Australia, Chile, Argentina & Japan
Netherlands, 2006Netherlands, 2006 80%80%
Australia, 2004Australia, 2004 64% 64%
Belgium, 2006Belgium, 2006 81%81%
Brazil, 2007Brazil, 2007 100%100%
Poland, 2004Poland, 2004 100%100%
Germany, 1998Germany, 1998 88%88%
Non-O157 Non-O157 STECSTEC surveillancesurveillance27 countries; 18,302 27 countries; 18,302 isolatesisolates% Non-O157 in the Enter-net database% Non-O157 in the Enter-net database
0%0%
10%10%
20%20%
30%30%
40%40%
50%50%
60%60%
70%70%
80%80%
90%90%
100%100%
CZCZ GRGR MTMT PLPL SKSK GBGB ESES GZGZ NZNZ IEIE NLNL EEEE SESE JPJP BEBE FRFR HUHU ATAT FIFI NONO CHCH ITIT LULU DKDK DEDE SISI ZAZA
7070 33 2020 1313 66
59495949
8787
15171517
607607642642457457 2727 510510
15761576
314314322322 4848 312312115115130130 1818 164164 4242 872872
42324232
246246 33
CountryCountry
Non-O157 Non-O157 STECSTEC surveillancesurveillance27 countries; 6,480 isolates27 countries; 6,480 isolates
O Groups in the Enter-net database O Groups in the Enter-net database
00
200200
400400
600600
800800
10001000
12001200
2626103
103
Non
-O15
7
Non
-O15
79191 14
514
5NTNT11
111
114
614
612
812
8
O rou
gh
O rou
gh11
311
35555 22 767617
717
7 88 5511
711
717
417
412
112
1
Oth
ers
Oth
ers
STEC incidences in EuropeSTEC incidences in Europe
Selected incidences of STECData from ”The Enter-net database”
0
2
4
6
2000 2001 2002 2003 2004 2005 2006
Cases
per
100.0
00/Y
r
ScotlandDenmarkIrelandE, W & NIGermanyBelgiumAustriaNetherlandsNorwayFinlandItaly
22
00
55
33
3232
33
00
55
88
2020
No casesNo cases
1 - 1 - 1,491,49
1,5 – 1,5 – 1,991,99
Incidence of Incidence of STEC STEC
(per 100.000)(per 100.000)
0 - 0,490 - 0,490,5 - 0,990,5 - 0,99
2 – 3,992 – 3,991313
1212
> 4> 4
STEC in DenmarkSTEC in Denmark20062006
2929
00
112525
Number of diagnosed STEC infections by county, and Number of diagnosed STEC infections by county, and annual incidence of annual incidence of allall STEC infections in 2006 STEC infections in 2006
12 !12 !
0,01,02,03,04,05,06,07,08,0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
RA
TIO
Detection ratio of STEC in counties using molecular methods vs "other methods" in Denmark
O22:H8O22:H8O26:H11O26:H11O103:H2O103:H2O103:H25O103:H25O104:H21O104:H21O111:H- / H2 / O111:H- / H2 /
H8H8
O113:H21O113:H21
O117:H4O117:H4O118:H2O118:H2O119O119O121:H19 / H21O121:H19 / H21O128:H2O128:H2O145:H-O145:H-O?:H19O?:H19
Citrobacter Citrobacter freundiifreundii
Non-O157 STEC outbreaks
O103:H25 outbreak in O103:H25 outbreak in NorwayNorway
HUS HUS ”outbreak” ”outbreak” notifiednotified
Date of onset of diseaseDate of onset of disease
HUS casesHUS casesDiarrhea casesDiarrhea cases
20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7 8 9 10 11 12
JanuaryJanuary FebruaryFebruary MarchMarch
7 8 9 103 4 5 6
O103 pos / O103 pos / stx2stx2 neg negstx2stx2 pos pos
Source: Sliced, Source: Sliced, dry dry fermented fermented lamb’s lamb’s sausagesausage
Product and environmental Product and environmental samplessamples
O103 positiveO103 positive
Cured meat productsCured meat products 24622462 5353Sheep meatSheep meat 171171 99EnvironmentEnvironment 296296 00Spices, additives, cultureSpices, additives, culture5757 00Minced meatMinced meat 10001000 00
All isolates were All isolates were stx2stx2 negative & negative & eaeeae pos.pos.BUT clustered with patient isolates by BUT clustered with patient isolates by MLVA (DNA fingerprint)MLVA (DNA fingerprint)
O26:H11 O26:H11 outbreak in outbreak in DenmarkDenmarkstx1 & eaestx1 & eae
20 cases; all children20 cases; all children
median 2 yearsmedian 2 years
Very mild symptomsVery mild symptoms
Discovered by PFGEDiscovered by PFGE
Little media attentionLittle media attention
17 cases; 15 children17 cases; 15 children
10 with HUS10 with HUS
1 child died 1 child died
HUS notificationHUS notification
Massive media Massive media attentionattention
O103:H25 O103:H25 outbreak in outbreak in NorwayNorwaystx2 & eaestx2 & eae
Lessons learned in NorwayLessons learned in Norway
• Outbreak Outbreak ddiscovered due to iscovered due to notification of cases of HUSnotification of cases of HUS
• Methods in clinical laboratories were Methods in clinical laboratories were inadeqaute for detection of non-O157 inadeqaute for detection of non-O157 in 5 out of the six first cases of HUSin 5 out of the six first cases of HUS
• stx2stx2 negative isolates dominated negative isolates dominated
• MLVA was used to identify cases and MLVA was used to identify cases and the sourcethe source
Lessons learned in Lessons learned in DenmarkDenmark
• Real-time PFGE of Danish non-O157 Real-time PFGE of Danish non-O157 detected a ”mild” outbreakdetected a ”mild” outbreak
• Only possible because isolates were Only possible because isolates were available for typingavailable for typing
Source identified usingSource identified using• access to purchase recordsaccess to purchase records• cooperation with supermarkets cooperation with supermarkets
searching their central computerssearching their central computers
HUS & STECHUS & STEC Australia, Australia, Cyprus, Denmark, Germany, Cyprus, Denmark, Germany,
77 Hungary, Japan, PolandHungary, Japan, Poland
Notification dates from 1998 – 2005Notification dates from 1998 – 2005
STEC onlySTEC only Austria, CanadaAustria, Canada, Estonia, , Estonia, Finland, Finland,
1313 Greece,Iceland, Ireland, Luxembourg, Greece,Iceland, Ireland, Luxembourg, Malta , Malta , New Zealand, Norway, Slovenia, New Zealand, Norway, Slovenia, Sweden Sweden
Notification dates from 1990 – 2005Notification dates from 1990 – 2005
Not mandatoryNot mandatory England & Wales, France †, Italy ‡,England & Wales, France †, Italy ‡,
77 Romania, Spain, Scotland*, South AfricaRomania, Spain, Scotland*, South Africa
Pediatric- nephrology network since Pediatric- nephrology network since
† † 1996 < 15 Yrs1996 < 15 Yrs ‡ 1988 < 14 Yrs‡ 1988 < 14 Yrs
*Laboratory based since mid-eight’ies*Laboratory based since mid-eight’ies
HUS and STEC notifications worldwide
SubtypeSubtype Non-HUS *Non-HUS * HUS*HUS*
stx2stx2 6060 1111
stx2cstx2c 4949 11
stx2dstx2d--activatableactivatable 44
stx2dstx2d 3939
stx2estx2e 22
stx2stx2--variantvariant 33
stx2stx2 + + stx2cstx2c 2323 77
stx2stx2 + + stx2dstx2d 11
2x 2x stx2stx2--activatableactivatable 44
stx2cstx2c + + stx2stx2--activatableactivatable 11
TotalTotal 186186 1919
Ethelberg et al. 2004 EID; 10Ethelberg et al. 2004 EID; 10
Shiga toxin 2 (Shiga toxin 2 (stx2stx2) subtype and clinical presentation) subtype and clinical presentation
stx2stx2 OR* 32.5 > OR* 32.5 > stx2cstx2c OR* 4.7 for HUS OR* 4.7 for HUS*) OR: odds ratio; multivariant analysis adjusted for age*) OR: odds ratio; multivariant analysis adjusted for age
Virulence profile and Virulence profile and clinical manifestation in clinical manifestation in 559 Danish 559 Danish STECSTEC patients 1994-2005 patients 1994-2005
0%
20%
40%
60%
80%
100%
stx2 +eae
stx1 +stx2 +
eae
stx1 +eae
stx2 stx1 +stx2
stx1
Other
D
PD
BD
PBD
HUS
Stx1 : 4 subtypes Stx1 : 4 subtypes aa - d - d7-8 variants7-8 variants
dd
bb
cc
aaStx1a-S._dysenteriae-3818T
Stx1a-S._sonnei-CB7888
Stx1b-O111-CB168
Stx1b-O157-EDL933
Stx1b-O48-94C
Stx1b-O111-PH
Stx1c-O174-DG131-3
Stx1d-ONT-MHI813
A1 A2 BBSP SP
Pairwise (OG:100%,UG:0%) (FAST:2,10) Gapcost:0%
VT1 translated sequences
10
0
99
98
97
96
Pairwise (OG:100%,UG:0%) (FAST:2,10) Gapcost:0% Disc. unk.
vtx_TRANSL
100
99
98
97
96
95
94
93
92
91
90
89
88
87
86
85
84
83
82
vtx2d-O157-7279
vtx2d-O174-EC1720a
vtx2d-O91-a-B2F1
vtx2d-O91-b-B2F1
vtx2d-O8-C466-01B
vtx2d-C_freundii-LM76..
vtx2d-O6-NV206
vtx2d-O22-KY-O19
vtx2d-O73-C165-02
vtx2a-O157-EDL933
vtx2a-O26-FD930
vtx2a-O157-SF
vtx2a-O48-94C
vtx2a-O26-126814
vtx2a-E_cloacae-95MV2
vtx2c-O157-E32511
vtx2c-O157-FLY16
vtx2c-O157-C394-03
vtx2c-O157-469
vtx2c-O174-b-031
vtx2g-O2-7v
vtx2g-O2-S86
vtx2g-Out-S-8
vtx2b-O111-S-3
vtx2b-O96-S-6
vtx2b-O22-3143-97
vtx2b-ONT-5293-98
vtx2b-O118-EH250
vtx2b-O16-6451-98
vtx2b-O174-a-031
vtx2b-O111-PH
vtx2e-O139-412
vtx2e-O22-3615-99
vtx2e-O101-E-D43
vtx2f-O128-T4-97
dd
ff
bb
ggcc
aa
ee
Stx2 :Stx2 :7 subtypes7 subtypesaa - - gg
35 variants35 variants
A1 A2 BBSP SP
A1 A2 BBSP SP
95 AA95 AA 64 AA 64 AA
VT2B VT2B VT2A VT2A
225225
Only 12 Stx2Only 12 Stx2 variants found variants found in Danish patientsin Danish patients
Stx2aStx2a
stx2cstx2c
stx2dstx2d
stx2estx2e
stx2gstx2g
stx2bstx2b
Stx2a-O48-94CStx2a-O48-94C
Stx2a-O157-EDL933Stx2a-O157-EDL933
Stx2c-O157-FLY16Stx2c-O157-FLY16
Stx2d-O8-C466-01BStx2d-O8-C466-01B
Stx2d-O157-7279Stx2d-O157-7279
Stx2e-ONTStx2e-ONT-26725-97-26725-97
Stx2g-O2-7vStx2g-O2-7v
Stx2b-O118-EH250Stx2b-O118-EH250
0.010.01
Stx2c-O157-C394-03Stx2c-O157-C394-03
Stx2d-O73-C165-02Stx2d-O73-C165-02
Stx2e-O101-E43Stx2e-O101-E43
Stx2b-O111-PHStx2b-O111-PH
New variantsNew variants
First time in First time in humanshumans
Attack rate of Stx2 variants Attack rate of Stx2 variants associated with HUSassociated with HUS
O157O157
Stx2a-O157-EDL933 + Stx2c-O157-FLY16Stx2a-O157-EDL933 + Stx2c-O157-FLY16 6/236/23
26%26%
Stx2a-O157-EDL933Stx2a-O157-EDL933 3/173/17 18%18%
Stx2c-O157-FLY16Stx2c-O157-FLY16 1/181/18 6%6%
Stx2a-O157-SF + Stx2c-O157-FLY16Stx2a-O157-SF + Stx2c-O157-FLY16 1/11/1 --
Non-O157Non-O157
Stx2a-O48-94CStx2a-O48-94C 6/206/20 30%30%
Stx1b + Stx2a-O157-EDL933Stx1b + Stx2a-O157-EDL933 1/31/3 --
Stx2a-O157-EDL933 +Stx2a-O157-EDL933 + Stx2c-O157-FLY16Stx2c-O157-FLY16 1/21/2 --
Stx1b + Stx2a-O48-94CStx1b + Stx2a-O48-94C 1/51/5 20%20%
ConclusionsConclusionsTwo Stx2aTwo Stx2a variants associated with HUSvariants associated with HUS
Stx2a-O157-EDL933Stx2a-O157-EDL933 in NSF O157in NSF O157(& Stx2-O157-FLY16)(& Stx2-O157-FLY16)
Stx2a-O157-SF Stx2a-O157-SF in SF O157in SF O157Stx2a-O48-94CStx2a-O48-94C in in Non-O157Non-O157
New Paradigm:New Paradigm:
How may STEC be classified?How may STEC be classified?
Are certain virulence ”cocktails” associated with Are certain virulence ”cocktails” associated with severe disease rather than the serotype?severe disease rather than the serotype?
Based on the reported occurrence of serotypes in human Based on the reported occurrence of serotypes in human disease, in outbreaks and/or in hemolytic-uremic syndrome (HUS)disease, in outbreaks and/or in hemolytic-uremic syndrome (HUS)
Classification of STEC in 5 Sero-Classification of STEC in 5 Sero-pathotypespathotypesKarmali Karmali et al.et al. , 2003, J. Clin. Microbiol., 41:4930-40 , 2003, J. Clin. Microbiol., 41:4930-40
Sero-Sero-pathotypepathotype
Relative Relative incidence incidence
Frequency Frequency of of
involvement involvement in outbreaksin outbreaks
Association Association with severe with severe
disease disease (HUS or HC)(HUS or HC)
SerotypesSerotypes
AA HighHigh CommonCommon YesYes O157:H7, O157:NMO157:H7, O157:NM
BB ModerateModerate UncommonUncommon YesYes O26:H11, O103:H2, O26:H11, O103:H2, O111:NM, O121:H19,O111:NM, O121:H19,O145:NMO145:NM
CC LowLow RareRare YesYes O91:H21, O113: H21, O91:H21, O113: H21, O104:H21, othersO104:H21, others
DD LowLow RareRare NoNo multiplemultiple
EE Non Non human human only only
multiplemultiple
New ParadigmNew Paradigm
Problems with this Problems with this classificationclassification
Association with serotype and not with Association with serotype and not with virulence profilevirulence profile
• More than 120 O:H serotypes have been More than 120 O:H serotypes have been associated withassociated withHUS (Bergey’s Manual of Systematic Bacteriology, HUS (Bergey’s Manual of Systematic Bacteriology, 2nd ed.)2nd ed.)
• Many O:H serotypes display extensive Many O:H serotypes display extensive heterogeneityheterogeneity
Involvement in outbreak may rapidly changeInvolvement in outbreak may rapidly change
Relative incidence Relative incidence • is scewed by lack of effecient detection methodsis scewed by lack of effecient detection methods• will vary depending on the epidemiology of will vary depending on the epidemiology of
specific typesspecific types
New ParadigmNew Paradigm
1.1. HUS inducing STEC and/or an epidemic outbreak potentialHUS inducing STEC and/or an epidemic outbreak potential
• eaeeae and and stx2astx2a• eaeeae negative and negative and stx2dstx2d (activatable) (activatable)• eaeeae and and stx1stx1 Less common but certain O:H serotypes Less common but certain O:H serotypes
have have been associated with HUSbeen associated with HUS
2.2. Diarrhea inducing in humans!Diarrhea inducing in humans!
• Many different virulence profilesMany different virulence profiles• Capacity to produce Stx and association with diarrhea in Capacity to produce Stx and association with diarrhea in
humanshumans
3.3. Animal-associated STECAnimal-associated STEC
• High prevalence in the animal reservoirHigh prevalence in the animal reservoir• Seems to be their natural habitat Seems to be their natural habitat • No human casesNo human cases• Candidates for this group are Candidates for this group are stx2estx2e positives positives
Alternative Alternative classificationclassification
New ParadigmNew Paradigm
QuestionsQuestions
Should management and Should management and treatment of patients be treatment of patients be
adjusted according to adjusted according to virulence cocktail?virulence cocktail?
New ParadigmNew Paradigm
Danish Practice since 2000Danish Practice since 2000ALL patients with STEC are excludedALL patients with STEC are excludedor quarantined if they areor quarantined if they are
• Children in institutions and day careChildren in institutions and day care• Staff of health care facilitiesStaff of health care facilities• Hospital staff or hospitalized patientsHospital staff or hospitalized patients• Food handlersFood handlers
BackgroundBackground
and until they have had two and until they have had two consecutive STEC negative stool consecutive STEC negative stool samples samples
Prolonged shedding of STEC has Prolonged shedding of STEC has resulted in huge social problems resulted in huge social problems especially for parentsespecially for parents
Danish example of Danish example of consequencesconsequencesRevision of guidelines for treatment of Revision of guidelines for treatment of Danish patients with STEC may include Danish patients with STEC may include antibiotic treatment of asymptomatic antibiotic treatment of asymptomatic patients with patients with
• eaeeae negative STEC negative STEC• eaeeae & & stx1stx1 - except some serotypes - except some serotypes
Asymptomatic patients are likely to be Asymptomatic patients are likely to be allowed back in institutions and day care allowed back in institutions and day care after treatmentafter treatment
New ParadigmNew Paradigm
• Adequate detection methods should include the isolation of Adequate detection methods should include the isolation of bacteriabacteria
• Typing methods should be standardizedTyping methods should be standardized
• Subtyping methods for Stx2aSubtyping methods for Stx2a variants associated with HUS variants associated with HUS should be implementedshould be implemented
• Urgent need for standardized nomenclatureUrgent need for standardized nomenclature
RecommendationsRecommendations
QuestionsQuestions1.1. How much is detection and How much is detection and
surveillance scewed?surveillance scewed?
2.2. Can case definitions for HUS to Can case definitions for HUS to be notified within the Public be notified within the Public Health system be established?Health system be established?
3.3. Will management and treatment Will management and treatment of STEC patients depend onof STEC patients depend on
• a case-to-case based a case-to-case based assessment? assessment?
• an outbreak-to-outbreak an outbreak-to-outbreak approach?approach?
• local epidemiology?local epidemiology?
QuestionQuestion
Should non-O157:H7 Should non-O157:H7 STECs be considered to STECs be considered to be adulterants as be adulterants as E. coliE. coli O157:H7? O157:H7?
YES - someYES - some
AcknowledgementsAcknowledgementsStatens Serum Institut, CopenhagenStatens Serum Institut, CopenhagenJoan Neverman Jensen Joan Neverman Jensen Søren PerssonSøren PerssonKatharina E. P. OlsenKatharina E. P. Olsen
Co-authors on nomenclatureCo-authors on nomenclatureLothar Beutin, Lothar Beutin, Federal Institute for Risk Federal Institute for Risk Assessment, BerlinAssessment, Berlin
Denis Piérard, Denis Piérard, Academisch Ziekenhuis Vrije Academisch Ziekenhuis Vrije Universiteit, BrusselsUniversiteit, Brussels
Nancy A. Strockbine, Nancy A. Strockbine, National Center National Center for Zoonotic, Vector-borne and Enteric Diseases for Zoonotic, Vector-borne and Enteric Diseases (CDC), Atlanta(CDC), Atlanta
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